RGD-grafted dextran methacrylate hydrogel incorporating osteogenic peptide and Mn3O4 nanozymes for enhanced bone defect healing

Aggressive inflammation triggered by excessive reactive oxygen species (ROS) seriously disrupts intercellular communication between macrophages and tissue regenerative cells, such as bone marrow mesenchymal stem cells (BMSCs) and vascular endothelial cells, thereby delaying the healing process. Modulating the immune microenvironment through biomaterial-based strategies is crucial for effective healing. In this study, we constructed a composite hydrogel (denoted as RGD@DEXMA/DOPA-P24/Mn₃O₄) by co-loading manganous-manganic oxide (Mn₃O₄) nanozyme and 3,4-dihydroxyphenylalanine-modified osteogenic peptide P24 (DOPA-P24) into arginine-glycine-aspartic acid (RGD)-grafted dextran methacrylate (DEXMA) hydrogel. The Mn₃O₄ nanozymes effectively regulated the immune microenvironment by scavenging intracellular ROS and inducing M1-to-M2 macrophage polarization. This immunoregulatory capability synergistically enhances angiogenesis, providing essential metabolic support for improved osteogenesis. The RGD sequence endowed the hydrogel with excellent adhesive properties for BMSCs, promoting cellular proliferation. In combination with DOPA-P24, the DOPA moiety facilitated the sustained release of P24, inducing the osteogenic differentiation of BMSCs over time. By alleviating inflammation, promoting neovascularization, and enhancing bone formation, the RGD@DEXMA/DOPA-P24/Mn₃O₄ hydrogel accelerated the regeneration of bone defects <i>in vivo</i>. This work presents a novel strategy to enhance bone healing through synergistic immunomodulatory and osteogenic effects mediated by multifunctional bone scaffolds.